audit in pharmacovigilance

Pharmacovigilance Risk Management

Audit

What is an Audit?A systematic and independent examination of activities to determine whether the evaluated activities were performed according to defined requirements.*

Key Words in DefinitionSystematic –organized, methodical, plannedIndependent –unbiased, no conflict of interest, objectiveExamination –assessment, evaluation, investigationDefined requirements –audit criteria, regulations, procedures

*This definition compiled from an extraction of ICH and ISO definitions.

Audits

Why Perform Pharmacovigilance System Audits?To ensure compliance with company procedures and local / global regulatory requirementsTo ensure company regulatory obligations / commitments are metEvolving regulatory requirementsIncreasing Regulatory Inspections –Internal detection of risk is essentialTo identify process / quality improvements

Pharmacovigilance System Audits

MOST IMPORTANTLY, PHARMACOVIGILANCE AUDITS ACT AS ONE MECHANISM TO ENSURE THE SAFETY OF PATIENTS IS MAINTAINED

Types of Pharmacovigilance System Audits

Global Pharmacovigilance systems/processesCompany Affiliates (i.e., Country Office, Local Operating Company, Marketing Company)Marketing (Licensing) Partners


Global Pharmacovigilance System AuditsFocus on central Pharmacovigilance processes–Safety Case Processing–Expedited Reporting–Signal Detection / Safety Surveillance–Aggregate Reports (e.g., PSUR, PADER, etc.)–Literature Search–Office of the QPPV responsibilitiesAssess compliance with company procedures and global Pharmacovigilance regulationsSample of products across therapeutic areas and a defined timeframe (vehicle to assess the system / process)Systems approach focused on processes


Company AffiliatesPrimary focus on local Pharmacovigilance responsibilities

Assess compliance with local and global company procedures and regulatory requirements (as applicable)

Evaluate the flow of safety information (from all applicable sources) from initial receipt to reporting to external parties

Involves many functional groups that impact the Pharmacovigilance system-Pharmacovigilance -Sales-Regulatory Affairs -Product Quality-Medical/Clinical -Information Technology-Marketing -Medical Information

Not just an audit of local affiliate but also of global processes to support local affiliates


Company Affiliates (continued)Topics most often covered within scope:–Adverse event collection and processing–Expedited reporting to regulatory authorities–SUSAR distribution–Product Quality Complaint handling–Safety surveillance–Local quality systems (including compliance monitoring)–Regulatory functions (e.g., Aggregate reports submission, Labeling, Regulatory Authority query management, etc.)–Contracts and Agreements (Marketing Partners, CROs, etc.)–Medical Information–Promotional Material–Standard Operating Procedures (SOPs)–Training–Document Retention / Archive–Electronic systems used to support the Pharmacovigilance system–Business Continuity / Disaster Recovery


Marketing (Licensing) Partner Audits

Includes in-licensed and out-licensed product agreements

Focus on compliance with Marketing Partner agreement –Ensure Pharmacovigilance roles and responsibilities are defined and performed –Ensure appropriate exchange of safety information

Assess compliance with local and global company procedures and regulatory requirements (as applicable)

May be performed independently by company, as a joint audit between companies, or by an agreed upon consultant

While not an audit, Pharmacovigilance Quality Assurance Organizations may contribute to Licensing and Acquisition Due-Diligence assessments


Risk Management / Audit Scheduling

Identify universe of company Pharmacovigilance systems, affiliates, and marketing partners

Identify critical risk factors / indicators* to measure each entity in the universe–Volume of Adverse Event Cases–Clinical Trial Activity–Number of External Contracts / Agreements–Previous Audit / Inspection History–Compliance data

Receive input from key stakeholders on proposed schedule (e.g., Head of Safety, QPPV, Regional Safety Representatives, etc.)

Communicate forward-looking schedule to global audience

*Risk factors / indicators may differ for Global Pharmacovigilance Systems, Affiliates and Marketing Partners

PV System Audit Program Fundamentals


Timeframes for each of these audit phases may vary based on company procedures, type of audit, and defined scope.

Audit Planning and PreparationPre-audit meetings to understand organization and scope of processes

Identification of system owners

Development and agreement of an audit plan defining audit objectives, scope and roles/responsibilities

Pre-audit document requests to provide framework for regulatory environment and audit conduct strategy (e.g., sampling strategy, interviews, etc.)

Development and agreement of audit agenda defining topics and personnel involved along with proposed time*

*Agendas generally require flexibility


Audit ConductOpening / Introductory Meeting to “kick off” the auditInterviews with relevant personnelDocument reviewsDemonstration of activities (e.g., processing of an adverse event case)Tour of facilities (e.g., work areas, file storage and archiving)Closing / Exit meeting to discuss preliminary resultsFollow-up on outstanding questions / requests


Audit ReportingAudit report issued within defined timelines –Executive Summary –Description of Objectives and Scope of audit –Observations »Clear description of conditions observed »Reference or criteria as the basis for the observation »Quantification / Examples for context (as applicable) »Assessment of cause and effect »Judgment / Rating (e.g., Critical, Major, Minor, etc.) based on company … . rating scale –Process / Quality Improvement Opportunities


Corrective and Preventative Action (CAPA)Understand the observation and seek clarification as neededAssess root cause / underlying issueDevelop CAPAs that are:–Specific: Action resolves the issue and aims to prevent reoccurrence–Achievable: Action that is realistic and in accordance with regulations–Time Driven: Identify realistic timeframe for completion (based on risk)–Accountable: Action has clear accountability definedCAPA development is one of the most important aspects of successful audits


Audit Follow-up and ClosurePeriodic follow-up on open CAPAs until closure (may be risk based)Confirmation or verification of completion may be required (may be risk based)Audit closure when applicable CAPAs have been completedUtilize audit experience to build a culture of continuous improvement and audit / inspection readiness


MetricsAggregate analysis of audit results over a defined time periodVery effective business tool to summarize company’s risk profile and compliance status (based on audits)Focus on most common critical deficiencies (trends) and implement global resolutions to prevent re-occurrenceMechanism to evaluate the effectiveness of improvement initiatives


Global Pharmacovigilance Inspection Trends

Inspection Readiness

Preparing for Inspections –Best PracticesAnticipate an inspection–Comply with company procedures and external regulations on an ongoing basis–Maintain current and historical procedures/guidelines–Ensure documentation is available, accurate and complete on an ongoing basis–Ensure personnel training is current–Maintain awareness of contracted functionsHave a company / site inspection plan (and routinely test it)–Identify a core inspection team–Maintain a key contacts list including primary and back-up contacts–Address logistical and administrative aspects (rooms, technology, etc.)Inspection readiness training for company personnelMock Inspections / Mock Interviews


During the Inspection –Best PracticesRelax, don’t panic!Be polite, cooperative, confident, and professionalEscort the inspector at all timesDon’t underestimate the amount of questions and paper involvedKeep track of all questions and requests (daily notes)Ask for clarification to questions and /or requests you do not understandMaintain a log of all documents requested and keep copies of all documents provided to the Inspector(s)–Indicate which documents were provided, reviewed and retained by the Inspector(s)Clarify misunderstandings in real-time as they occur


After the Inspection –Best PracticesExit Meeting–Ensure appropriate company personnel are present for Exit Meeting–Clarify misunderstandings–Confirm reporting and response procedures–Communicate corrective actions implemented during the inspection

Don’t wait for an inspection report to begin addressing identified non-compliances

Formulate a coordinated response with input from relevant parties–Key system owners (Subject Matter Experts)–Quality Assurance–Legal

Consider impact of response on global or local operations


Are you Inspection Ready?Do you have an inspection plan and contact list (and routinely test it)?

Do you have procedures in place?–Are they current?–Are they retrievable?

Do you report, process, and submit adverse events (from all potential sources) within required timelines?

Do you comply with company procedures and applicable regulations?

Are your staff qualified and trained?

Do you have quality systems in place to ensure data / process quality?

Do you know where your documentation is maintained?

Are active relationships in place with other relevant functional areas (e.g., Manufacturing, Clinical/Medical, Marketing, Sales, etc.)?


Many components to the Pharmacovigilance System–All very important contributors–Many linkages across the organization / disciplines / functional lines

Internal pharmacovigilance audits are integral to assure company compliance and are a key success factor for Inspection Readiness

Pharmacovigilance audit programs should be designed to deliver value by:–Minimizing company risk–Identifying opportunities for improvement

Promote continuous improvement culture within organizations where:–Audits are part of routine business–Total Quality Management (TQM) tools and principles are utilized

Sustain Inspection Readiness–Maintain awareness of regulatory trends (e.g., Global / Local Regulations, Inspections, etc.)–Do everything in anticipation and preparation for an inspection–Documentation is essential

Summary

audit in pharmacovigilance

Business

pharmacovigilance audits

pharmacovigilance roles

global company procedures

audit objectives

audit planning

type of audit

audit phases

joint audit